Autophagy is a cellular process that involves the formation of an isolated membrane to form double membrane vesicles (autophagosomes) that sequesters the cytoplasmic materials. Followed by fusion of the autophagosome with lysosome to form an autolysosome, all the engulfed materials are degraded by lysosomal hydrolases to recycle intracellular nutrients and energy [1, 2]. Autophagy-lysosome and ubiquitin-proteasome pathways are the two major protein degradation pathways in cells [3]. While short-lived nuclear and cytosolic proteins are degraded by proteasomes, large membrane proteins, oligomers and aggregates which cannot pass through the narrow pore of the proteasome barrel are degraded by autophagy [4].
A variety of neurodegenerative diseases are caused by toxic, aggregate-prone or oligomeric proteins [5-9]. For example, Huntington's disease (HD) is caused by an over 35 CAG trinucleotide repeat expansion, which results in a long mutant polyQ tract in the huntingtin protein. These polyQ expansions are highly associated with the aggregate formation and toxicity [10, 11]. Autophagy, however, can reduce mutant huntingtin protein levels and its toxicity in cell and mouse models [6, 7]. Parkinson disease (PD) is caused by A53T or A30P α-synuclein mutants, which are identified as substrates of autophagy, and the clearance of these mutant proteins are also highly dependent on autophagy for removal [6-8, 11-14]. Pharmacological activation of autophagy reduces the levels and toxicity of mutant huntingtin, mutant proteins in spinocerebellar ataxia, mutant α-synuclein and mutant tau in either mouse or drosophila models [5, 15]. Furthermore, autophagy-related gene (ATG) knockdown leads to aggregate formation and toxicity in C.elegans [16, 17]. In addition to the formation of protein aggregates, the accumulation of abnormal mitochondria or endoplasmic reticulum, and an increase in the size and number of lipid droplets were observed in ATG gene knockout animal models [14, 18-20].